Alzheimer's genes: Are you at risk?

Several genes have been associated with Alzheimer's disease, but more research is needed.

By Mayo Clinic Staff

Certain genes make you more likely to develop Alzheimer's disease.

Genes control the function of every cell in your body. Some genes determine basic characteristics, such as the color of your eyes and hair. Other genes can make you more likely to develop certain diseases, including Alzheimer's disease.

Researchers have identified a number of genes associated with Alzheimer's disease. Some genes increase your likelihood of developing the disease (risk genes). Others guarantee that you will develop a disease (deterministic genes), though these are rare. However, genetic risk factors are just one of the factors involved in getting Alzheimer's disease.

Most common late-onset Alzheimer's gene

The most common type of Alzheimer's disease usually begins after age 65 (late-onset Alzheimer's disease). The most common gene associated with late-onset Alzheimer's disease is a risk gene called apolipoprotein E (APOE).

APOE has three common forms:

  • APOE e2 — the least common — reduces the risk of Alzheimer's.
  • APOE e4 — a little more common — increases the risk of Alzheimer's and is associated with getting the disease at an earlier age. Approximately 15% to 25% of the general population carries an APOE e4 allele.
  • APOE e3 — the most common — doesn't seem to affect the risk of Alzheimer's

Genes aren't the only factor

Because you inherit one APOE gene from your mother and another from your father, you have two copies of the APOE gene. Having at least one APOE e4 gene increases your risk of developing Alzheimer's disease two- to threefold. If you have two APOE e4 genes, your risk is even higher, approximately eight- to twelvefold.

But not everyone who has one or even two APOE e4 genes develops Alzheimer's disease. And the disease occurs in many people who don't even have an APOE e4 gene, suggesting that the APOE e4 gene affects risk but is not a cause. Other genetic and environmental factors likely are involved in the development of Alzheimer's disease.

Other late-onset genes

As research on the genetics of Alzheimer's progresses, researchers are uncovering links between late-onset Alzheimer's and a number of other genes. Several examples include:

  • ABCA7. The exact role of ABCA7 isn't clear, but the gene seems to be linked to a greater risk of Alzheimer's disease. Researchers suspect that it may have something to do with the gene's role in how the body uses cholesterol.
  • CLU. This gene helps regulate the clearance of amyloid-beta from the brain. Research supports the theory that an imbalance in the production and clearance of amyloid-beta is central to the development of Alzheimer's disease.
  • CR1. A deficiency of the protein this gene produces may contribute to chronic inflammation in the brain. Inflammation is another possible factor in the development of Alzheimer's disease.
  • PICALM. This gene is linked to the process by which brain nerve cells (neurons) communicate with each other. Smooth communication between neurons is important for proper neuron function and memory formation.
  • PLD3. Scientists don't know much about the role of PLD3 in the brain. But it's recently been linked to a significantly increased risk of Alzheimer's disease.
  • TREM2. This gene is involved in the regulation of the brain's response to inflammation. Rare variants in this gene are associated with an increased risk of Alzheimer's disease.
  • SORL1. Some variations of SORL1 on chromosome 11 appear to be associated with Alzheimer's disease.

Researchers are continuing to learn more about the basic mechanisms of Alzheimer's disease, which may potentially lead to new ways to treat and prevent the disease.

As with APOE, these genes are risk factors, not direct causes. In other words, having a variation of one of these genes may increase your risk of Alzheimer's. However, not everyone who has one will develop Alzheimer's disease.

Young-onset Alzheimer's

A very small percentage of people who develop Alzheimer's disease have the young-onset type. Signs and symptoms of this type usually appear between ages 30 and 60 years. This type of Alzheimer's disease is very strongly linked to your genes.

Scientists have identified three genes in which mutations cause early-onset Alzheimer's disease. If you inherit one of these mutated genes from either parent, you will probably have Alzheimer's symptoms before age 65. The genes involved are:

  • Amyloid precursor protein (APP)
  • Presenilin 1 (PSEN1)
  • Presenilin 2 (PSEN2)

Mutations of these genes cause the production of excessive amounts of a toxic protein fragment called amyloid-beta peptide. This peptide can build up in the brain to form clumps called amyloid plaques, which are characteristic of Alzheimer's disease. A buildup of toxic amyloid-beta peptide and amyloid plaques may lead to the death of nerve cells and the progressive signs and symptoms of this disorder.

As amyloid plaques collect in the brain, tau proteins malfunction and stick together to form neurofibrillary tangles. These tangles are associated with the abnormal brain functions seen in Alzheimer's disease.

However, some people who have early-onset Alzheimer's don't have mutations in these three genes. That suggests that some early-onset forms of Alzheimer's disease are linked to other genetic mutations or other factors that haven't been identified yet.

One of the active research trials is the Dominantly Inherited Alzheimer Network (DIAN), which studies individuals with dominant Alzheimer's mutations (PSEN1, PSEN2 or APP). This research network includes observational studies and clinical trials.

Genetic testing

Most experts don't recommend genetic testing for late-onset Alzheimer's. In some instances of early-onset Alzheimer's, however, genetic testing may be appropriate.

Most clinicians discourage testing for the APOE genotype because the results are difficult to interpret. And doctors can generally diagnose Alzheimer's disease without the use of genetic testing.

Testing for the mutant genes that have been linked to early-onset Alzheimer's — APP, PSEN1 and PSEN2 — may provide more-certain results if you're showing early symptoms or if you have a family history of early-onset disease. Genetic testing for early-onset Alzheimer's may also have implications for current and future therapeutic drug trials as well as for family planning.

Before being tested, it's important to weigh the emotional consequences of having that information. The results may affect your eligibility for certain forms of insurance, such as disability, long-term care and life insurance.

Researchers and genes

Researchers suspect that many more genes that haven't been identified yet affect the risk of Alzheimer's disease. Such information may prove vital in the development of new ways to treat, or even prevent, Alzheimer's disease in the future.

Researchers are also studying genes that may protect against Alzheimer's disease. One variant of the APOE gene, called APOE Christchurch, appears to be protective, with an effect similar to that of APOE e2. More research is needed to understand this variant's effect on Alzheimer's disease risk.

The Alzheimer's Disease Genetics Study, sponsored by the National Institute on Aging, is examining genetic information from families that have at least two living family members who have developed Alzheimer's after age 65. If your family is interested in participating in this study, visit the website for the National Cell Repository for Alzheimer's Disease.

A number of other studies are evaluating the genetics of people with Alzheimer's disease and their family members. To learn more about these studies, and whether or not they're recruiting volunteers, visit the National Institute on Aging's Alzheimer's Disease Education and Referral Center website, or ask your doctor what trials might be available.

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May 06, 2021 See more In-depth

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